The present invention relates to a method for preparing halomethyl heterocyclic compounds, especially 5- and 6-halomethyl quinoxalines.
The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with respect to its practice are incorporated herein by reference and, for convenience, are numerically referenced in the following text and respectively grouped in the appended bibliography.
Quinoxaline-6-carboxylic acid is an important chemical intermediate for the preparation of compounds such as AMPHAKINE CX516(copyright) [1-(quinoxalin-6-ylcarbonyl) piperidine], a drug being tested for the treatment of Alzheimer""s disease, Attention Deficit Hyperactivity Disorder (ADHD), Mild Cognitive Impairment (MCI), Chronic Schizophrenia and male sexual dysfunction (1). The preparation of AMPHAKINE CX516(copyright) involves the conversion of 3,4-diaminobenzoic acid to quinoxaline-6-carboxylic acid with sodium glyoxal bisulfite, followed by amidation of the resulting acid with piperidine, as set-out below (2, 12). 
Although the preparation of AMPHAKINE CX516(copyright) appears straightforward, the synthesis requires the use of 3,4-diaminobenzoic acid, an expensive starting material. For example, preparation of the isomeric 2,3-diaminobenzoic acid employs a multi-step method that includes oxidation, reduction, amidation, nitration, separation of isomers, further reduction, and hydrolysis, as set out below (3). Preparation of the isomeric 3,4-diaminobenzoic acid can be carried out using this multi-step method by isolating and further reacting the 3-amido, 4-nitrobenzoic acid isomer. 
Other methods for preparing 3,4-diaminobenzoic-acid involve the electrochemical reduction of 3,4-dinitrobenzoic acid and the hydrogenation of substituted benzofurazans (4). These methods also employ expensive chemical intermediates.
Initial attempts by the applicant to prepare quinoxaline-6-carboxylic acid focused on a one step selective oxidation of the benzyl group to a carboxylic acid without affecting the aromatic rings, as set out below. 
Many methods are known for the direct oxidation of benzylic methyl groups to carboxylic acids. These methods typically employ a strong oxidizing agent, such as potassium permanganate, that reacts with a methyl group providing the remainder of the molecule is not reactive to the oxidizing agent (5). Thus, toluene can be oxidized with potassium permanganate to benzoic acid without affecting the benzene ring (5). Catalytic methods are generally more acceptable for industrial scale because theses methods employ milder oxidizing agents, i.e., air or oxygen, to carry out the oxidation of benzylic methyl groups to the corresponding carboxylic acid (6). The oxidation of 5- and 6-methyl-quinoxalines to 5- and 6-quinoxaline-carboxylic acids is not so straightforward, however, because strong oxidizing agents, such as potassium permanganate, degrade the aromatic ring yielding 2,3-pyrazinedicarboxylic acid (7): 
Milder oxidizing agents, i.e., air or oxygen in the presence of a catalyst, on the other hand, have no effect on the benzylic methyl group of 5- or 6-methyl-quinoxaline. Air in the presence of a cobalt salt can oxidize toluene to benzoic acid (6) but does not oxidize methyl-quinoxaline to quinoxaline-carboxylic acid. Similarly, air and oxygen in the presence of a palladium or platinum catalyst are also ineffective (8). Most known oxidizing reagents are either too mild to react with methyl-quinoxalines or are too reactive causing structural changes. 
Because attempts to prepare quinoxaline-6-carboxylic acid via a one-step selective oxidation of the benzyl group were not successful, a two-step method to prepare quinoxaline-6-carboxylic acid was developed. In the first step, 6-methyl-quinoxaline is halogenated to provide a 6-halomethyl-quinoxaline intermediate. In the second step, the 6-halomethyl-quinoxaline intermediate is oxidized to the corresponding quinoxaline-6-carboxylic acid.
The present invention relates to a method for preparing 5- and 6-halomethyl quinoxalines (I). The method comprises contacting a 5- or 6-methyl quinoxaline (II) with a halogenating agent in the presence of a radical initiator in a solvent selected from the group consisting of fluorobenzene, difluorobenzenes, trifluorobenzenes, chlorobenzene, dichlorobenzenes, trichlorobenzenes, xcex1, xcex1, xcex1-trifluorotoluene and xcex1, xcex1, xcex1-trichlorotoluene, to form the respective 5- or 6-halomethyl quinoxaline (I). X is a halogen. 
The present invention also pertains to a method for preparing a halomethyl compound selected from the group consisting of: 
The method comprises contacting the methyl precursor compound of the respective halomethyl compound with a halogenating agent in the presence of a radical initiator in a solvent selected from the group consisting of fluorobenzene, difluorobenzenes, trifluorobenzenes, chlorobenzene, dichlorobenzenes, trichlorobenzenes, xcex1, xcex1, xcex1-trifluorotoluene and xcex1, xcex1, xcex1-trichlorotoluene, to form the respective halomethyl compound, wherein X is a halogen.
The present invention also pertains to a halomethyl compound selected from the group consisting of: 
X is a halogen.
The present invention also pertains to a method for preparing 6-bromomethyl quinoxaline. The method comprises contacting 6-methyl quinoxaline with N-bromosuccinimide in the presence of a radical initiator in 1, 2-dichloroethane to form 6-bromomethyl quinoxaline.
The present invention pertains to a two-step method for converting benzyl heterocyclic compounds to the corresponding carboxylic acid heterocyclic compounds. The two-step method is especially suitable for converting 5- and 6-benzyl quinoxalines to the corresponding quinoxaline-5- and 6-carboxylic acids. The 5- and 6-benzyl quinoxalines may be prepared from ortho-diaminotoluenes, such as 2,3- and 3,4-diaminotoluene, by condensation with sodium glyoxal bisulfite. The method for halogenating benzylic methyl groups may also be employed to halogenate a wide variety of heterocyclic compounds.
In the first step, 6-methyl-quinoxaline is halogenated to provide a 6-halomethyl-quinoxaline intermediate. 
In the second step, the 6-halomethyl-quinoxaline intermediate is oxidized to the corresponding quinoxaline-6-carboxylic acid. 
This second step is more fully described in a copending patent application entitled xe2x80x9cMethod For Preparing Heterocyclic-Carboxylic Acidsxe2x80x9d filed by applicant concurrently with the present patent application and assigned to the assignee of this application, which is hereby incorporated by reference.
As set out above, 5- and 6-benzyl quinoxalines may be prepared from ortho-diaminotoluenes, such as 2,3- and 3,4-diaminotoluene, by condensation with sodium glyoxal bisulfite. For example, 6-benzyl quinoxaline may be prepared by condensation of 3,4-diaminotoluene with sodium glyoxal bisulfite (9).
Because attempts to prepare quinoxaline-6-carboxylic acid via a one-step selective oxidation of the benzyl group were not successful, a two-step method to prepare quinoxaline-6-carboxylic acid was developed. In the first step, 6-methyl-quinoxaline is halogenated to provide a 6-halomethyl-quinoxaline intermediate. In the second step, the 6-halomethyl-quinoxaline intermediate is oxidized to the corresponding quinoxaline-6-carboxylic acid.
In the first step of the synthesis, a benzylic heterocyclic compound and a halogenating agent, such as N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS), are reacted in the presence of a radical initiator, such as benzoyl peroxide or azobisisobutyronitrile, in a suitable solvent, to form the respective halomethyl heterocyclic compound, such as a 5- or 6-halomethyl quinoxaline (I). Suitable solvents may be selected from the group consisting of fluorobenzene, difluorobenzenes, trifluorobenzenes, chlorobenzene, dichlorobenzenes, trichlorobenzenes, xcex1, xcex1, xcex1-trifluorotoluene and xcex1, xcex1, xcex1-trichlorotoluene. 
The method for halogenating benzylic positions may also be employed to halogenate a variety of heterocyclic compounds. The method typically affords good yields of halomethyl-quinoxalines when [6QX]/[benzoyl peroxide]xe2x89xa640 while maintaining a temperature in the range of 60xc2x0 C. to 115 xc2x0C. for a period of 1 to 12 hours. Yields for benzylic brominations (conversionsxe2x89xa795%, selectivitiesxe2x89xa797%) are in general better than for benzylic chlorinations (conversions 60%, selectivities xcx9c75-80%). The 5- or 6-halomethyl quinoxaline may be a 5-halomethyl quinoxaline or may be a 6-halomethyl quinoxaline. The halomethyl may be a chloromethyl or may be a bromomethyl.
In one preferred embodiment, the invention is directed to a method for preparing 5- and 6-halomethyl quinoxalines (I). The method comprises contacting a 5- or 6-methyl quinoxaline (II) with a halogenating agent in the presence of a radical initiator in a solvent selected from the group consisting of fluorobenzene, difluorobenzenes, trifluorobenzenes, chlorobenzene, dichlorobenzenes, trichlorobenzenes, xcex1, xcex1, xcex1-trifluorotoluene and xcex1, xcex1, xcex1-trichlorotoluene, to form the respective 5- or 6-halomethyl quinoxaline (I), wherein X is a halogen. 
In another preferred embodiment, the invention is directed to a method for preparing a halomethyl compound selected from the group consisting of: 
The method comprises contacting the methyl precursor compound of the respective halomethyl compound with a halogenating agent in the presence of a radical initiator in a solvent selected from the group consisting of fluorobenzene, difluorobenzenes, trifluorobenzenes, chlorobenzene, dichlorobenzenes, trichlorobenzenes, xcex1, xcex1, xcex1-trifluorotoluene and xcex1, xcex1, xcex1-trichlorotoluene, to form the respective halomethyl compound, wherein X is a halogen.
Preferably, the halomethyl compound is selected from the group consisting of: 
The method comprises contacting the benzyl precursor compound of the respective halomethyl compound with a halogenating agent in the presence of a radical initiator in a solvent selected from the group consisting of fluorobenzene, difluorobenzenes, trifluorobenzenes, chlorobenzene, dichlorobenzenes, trichlorobenzenes, xcex1, xcex1, xcex1-trifluorotoluene and xcex1, xcex1, xcex1-trichlorotoluene, to form the respective halomethyl compound. X is a halogen.
The benzylic halogenation of heterocyclic compounds, such as methyl-quinoxalines, depends on a variety of factors including the halogenating agent, the radical initiator, the solvent, temperature, reaction time, reagent concentrations, and procedure.
The halogenating agents which may be employed in the present invention may be any halogenating agent which is capable of selectively halogenating the benzylic methyl group of a heterocyclic compound. The term xe2x80x9chalogenxe2x80x9d, as used herein, refers to the elements fluorine, chlorine, bromine, and iodine. Preferred halogens are chlorine and bromine. Non-limiting illustrative halogenating agents may be selected from the group consisting of N-chlorosuccinimide, N-bromosuccinimide, Cl2, Br2, t-butyl hypochlorite, N-chloroglutarimide, N-bromoglytarimide, N-chloro-N-cyclohexyl-benzenesulfonimide, and N-bromophthalimide. Preferred halogenating agents are N-chlorosuccinimide and N-bromosuccinimide.
The radical initiators which may be employed in the present invention may be any radical initiator which is capable of catalyzing the halogenating agent to selectively halogenate the benzylic methyl group of a heterocyclic compound. The presence of an initiator is essential for the reaction to occur because radicals propagate these reactions. Non-limiting illustrative radical initiator agents may be selected from the group consisting of benzoyl peroxide, azobisisobutyronitrile (AIBN), diacyl peroxides, dialkyl peroxydicarbonates, tert-alkylperoxyesters, monoperoxycarbonates, di(tert-alkylperoxy)ketals, and ketone peroxides. Preferred radical initiators are benzoyl peroxide and azobisisobutyronitrile. Alternatively, radicals can be generated photochemically.
The solvents which may be employed in the present invention may be any solvent which is capable of promoting the halogenating agent to selectively halogenate the benzylic methyl group of a heterocyclic compound. The choice of solvent is critical. The solvent must (a) be a media in which the halogenating agent has a low, but definite, solubility; (b) be stable to the halogenating agent allowing the halogenating agent to react preferentially at the methyl group of the heterocyclic compound to provide a halomethyl-heterocyclic compound that is stable in the solvent under the reaction conditions; and (c) be environmentally acceptable. Most conventional benzylic bromination procedures employ highly toxic solvents which are rigorously restricted on an industrial level. Suitable solvents may be selected from the group consisting of fluorobenzene, difluorobenzenes, trifluorobenzenes, chlorobenzene, dichlorobenzenes, trichlorobenzenes, xcex1, xcex1, xcex1-trifluorotoluene and xcex1, xcex1, xcex1-trichlorotoluene. Preferred solvents are chlorobenzene and xcex1, xcex1, xcex1-trifluorotoluene.
The temperatures which may be employed in the halogenation reactions of the present invention are important to ensure that the radical initiator decomposes to form radical chain-carriers. Thus, the optimum temperature will depend on the radical initiator used. The temperature should be chosen so that an optimum reaction rate can be reached. Such temperatures may range from about 50xc2x0 C. to about 120xc2x0 C., preferably from about 600xc2x0 C. to about 115xc2x0 C.
The reaction times which may be employed in the present invention play an important role on the selectivity of the product. Thus, reaction times should be optimum to ensure maximum conversion with best selectivities. Suitable reaction times may range from about 0.5 to about 12 hours, preferably from about 0.75 to about 4 hours. In most cases of benzylic brominations, side-reactions between N-bromosuccinimide (or N-chlorosuccinimide) with the aromatic ring are uncommon. In general, quinoxalines are not expected to react with N-bromosuccinimide and N-chlorosuccinimide by electrophilic aromatic substitution because the quinoxaline ring is known to be resistant to electrophilic attack (13).
The reagent concentrations which may be employed in the present invention may be stoichiometric or may be slightly higher in the halogenating agent concentration used. Although 5-(methyl)-quinoxaline reacted almost to completion in both acetonitrile and acetic acid in the presence of an almost stoichiometric amount of N-bromosuccinimide ([NBS]/[5QX]=1.1), the 6-isomer seems less reactive and does not easily reach completion under similar conditions. Typically, 80% conversion and 94% selectivity for 6-(bromomethyl)-quinoxaline can be accomplished under almost stoichiometric conditions ([NBS]/[5QX]=1.1) but with higher N-bromosuccinimide concentrations (i.e., [NBS]/[5QX]=1.5) yields can be improved (conversion xe2x89xa794%, selectivity xe2x89xa797%) to reach almost completion.
Products that can be made by this method are 6-(bromomethyl)-quinoxaline, 6-(chloromethyl)-quinoxaline, 5-(bromomethyl)-quinoxaline and 5-(chloromethyl)-quinoxaline. Other products that can be made by this method are: 4- and 5-(bromomethyl)-benzotriazole, 4- and 5-(chloromethyl)-benzotriazole, 4- and 5-(bromomethyl)-benzimidazolone, 4- and 5-(chloromethyl)-benzimidazolone. Other nitrogenous heterocyclic compounds that can be halogenated using this method include xcex1- and xcex3-picoline, quinaldines, methylphenanthridine. 
In another specific embodiment, the present invention is directed to a halomethyl compound selected from the group consisting of: 
wherein X is a halogen.
Preferably the halomethyl compound is selected from the group consisting of: 
Throughout this disclosure, applicant will suggest various theories or mechanisms by which applicant believes the present methods function. While applicant may offer various mechanisms to explain the present invention, applicant does not wish to be bound by theory. These theories are suggested to better understand the present invention but are not intended to limit the effective scope of the claims.